Stable aqueous isoproteronol compositions



United States Patent 3,039,928 STABLE AQUEOUS ISOPROTERONOL COMPOSITIONS Henry M. N. Dickinson, Lake Bluff, Ill., assignor to Abbott Laboratories, North Chicago, 111., a corporation of Illinois No Drawing. Filed Mar. 17, 1960, Ser. No. 15,548

6 Claims. (Cl. 167-65) This invention relates to novel compositions containing the well-known bronchodilator, isoproteronol. In particular, this invention is concerned with composition forms wherein said isoproteronol is maintained in stable form over extended periods of time.

Isoproteronol has been known to the art for many years as a useful bronchodilator or a medicament of particular applicability to the treatment of asthma. Isoproteronol is identified by the chemical name, a-(isopropylaminomethyl) protocatechuyl alcohol. This foregoing bronchodilator is most usefully employed to relieve bronchial constrictions and has attained widespread use and high popularity both among physicians and distressed patients. The beneficial properties of this active ingredient do not reside in permanent relief or cure of the afliiction, but in temporary relief; consequently, the asthmatic must repeatedly administer isoproteronol to himself during the periods of demand. It can beseen fromthe foregoing discussion that a composition form is desired which is readily and conveniently administered to the distressed subject. One of the means used to administer this beneficial medicament has been a mechanical inhalator. The mechanical inhalator is a closed body section having an open end which is designed to be placed in the mouth of the patient The body section, at the other extremity, usually has a constricted portion which separates a substantially bulbar-shaped body from the remaining body section. In the bulbar-sliaped body, there is a small weight which can be placed in motion by suction, and in the constricted portion, there is a cartridge containing the isoproteronol.- The patient places the open end of the apapratus in his mouth, inhales forcibly, causing the small weight to be placed in motion and thereby striking the cartridge to release the isoproteronol therefrom. It is apparent that this method of administering isoproteronol has many disadvantages, among which can be numbered inefiicient introduction of the active ingredient to the bronchials, aggravated physical stress on an already distressed patient and general awkwardness in handling and manipulation.

Attempts have been made to place isoproteronol in aqueous compositions, for such compositions have the advantage of easy oral administration. The problem that confronted the art in preparing such compositions is the instability of isoproteronol in aqueous composition. Thus, an aqueous composition containing isoproteronol will assume a darker color which indicates breakdown of the active ingredient. The rate of this breakdown can be substantially advanced in hours or days, depending on the concentration of the active ingredient in the aqueous composition and the absence or presence of substances designed to inhibit such breakdown. One aqueous composition of limited success contains sodium metabisulfite in a water solution of isoproteronol. The stability of such water solutions is extended, but degradation of isoproteronol still does occur. The sodium metabisulfite, itself, breaks down to sulfur dioxide gas and sodium sulfate. The sodium sulfate then undergoes transformation to sulfurous and sulfuric acids. Thus, such isoproteronol compositions can produce objectionable sulfur dioxide odors and an acid condition.

An object of this invention is the provision of composi- 3,03 9,928 Patented June 19,

tion forms wherein isoproteronol is maintained in stable form for extended periods of time.

A further object of this invention is to provide such stable compositions in forms which are efiiciently administered and pleasingly accepted.

A still further object of this invention is to provide a pleasingly acceptable syrup composition wherein isoproteronol is present in stable form for extended periods of time.

In the accomplishment of the foregoing objects and in accordance with the teachings of this invention, it is now provided that aqueous compositions in pleasingly acceptable syrup form can be prepared whereby the isopro teronol contained therein is kept stable by small amounts of ascorbic acid.

In accordance with the teachings of this description and the following examples, it has been surprisingly and unexpectedly discovered that ascorbic acid effectively prevents breakdown and deterioration of isoproteronol in aqueous compositions. Ascorbic acid is a known antioxidant and the peculiar properties of'this particular antioxidant are effective in attaining the objects of this invention.

The inherent properties of ascorbic acid are unique because many other antioxidants fail to display the beneficial properties of stabilizing isoproteronol. Among other antioxidants which have been found undesirable are butylated hydroxy anisole, propyl gallate, nor-dihydroguaretic acid, sodium metabisulfite, ethyl hydrocatfeate, di-tertbutyl-paracresol and others.

The useful properties of this invention are realized by incorporating at least about 0.05% weight/volume (w./v.) of ascorbic acid in an aqueous composition that contains a therapeutic amount of isoproteronol. The

therapeutic amount of isoproteronol in the composition can be from about 0.02% to about 0.25% w./v. A useful and preferred concentration of the antioxidant is about 0.1% w./v.; it should be understood that once the prescribed minimum range is exceeded, continual increases in the concentration will not deleteriously aifect the accomplishments of this invention. The upper limits of the antioxidant concentration will be determined by the obvious reluctance of the practitioner to add amounts in addition to that amount which accomplishes the desired object. The advantages of this invention can be attained by using ascorbic acid in a range of about 0.05% to about 0.25% w./v.

The pharmaceutical form of the syrups is prepared according to standard steps well known to the practitioner of this art. The teachings of this branch of the art pre-, scribe that sucrose and glucose can be used in varying concentrations depending on the thickness of the syrup ultimately desired. While glucose and sucrose can be used solely in preparing-operable syrups, the pharmacist prefers to employ them jointly in any one form because glucose imparts a more elegant feel to the syrup texture. Although the sugars can be used in a wide range of concentration, the preferred pharmaceutical forms illustrated hereinafter describe a combined glucose and sucrose concentration of about w./v., which concentration consists of about 50% sucrose and about 30% glucose.

The practice of this invention can be most simply embodied by a simple syrup solution containing an acid addition salt of isoproteronol in a therapeutic concentration of about 1% and the ascorbic acid in a concentration of about at least 0.5%. In actual and preferred practice, the foregoing simple syrup composition is complemented with various flavoring and coloring agents and other therapeutic additives such as expectorants (calcium iodide), mild stimulants and vasodilators (ephedrine) and mild sedatives (pentobarbital). Other agents, such as glycerin, can be added to give added body to the syrup.

It has also been found that when harsh-tasting expectorants, such as calcium iodide, are incorporated in the syrup, then artificial sweetening agents, such as sodium cyclamate (Sucaryl, Abbott) and sodium saccharin are very effective in masking the harsh taste of the expectorant. The large amounts of sucrose and glucose in the syrup compositions do not mask this harsh taste in the absence of the artificial sweetening agents.

The following examples are presented to illustrate various embodiments of the invention. It is understood that such examples do not represent and are not intended to represent exclusive embodiments; such examples serve merely to illustrate the practice of this invention.

Example I The following formulation is employed to prepare a straight syrup containing the active medicament and the stabilizing ascorbic acid. The Percent column relates to the given ingredient in terms of weight or volume per volume, and the Amount column relates to the absolute quantity of the ingredient in terms of either weight or volume.

Percent Ingredient Amount 0.06 Isoproteronol sulfate gm 0.6000 48.5 Sucrose gms 485.3250 31.2 Glucose gms 311.5500 0.1 Ascorbic acid gm 1.0000

Deionized water, q.s -ml 1000 The sucrose and glucose are dissolvedin about 200 ml. of deionized water. The ascorbic acid and isoproteronol are added and dissolved, and the volume is brought up to 1000 ml. with the addition of deionized Water. Dispersion of the solution is aided by stirring, and the solution is placed aside for continued observation at room temperature, and at 40 F. No discoloration is noted which indicates that the isoproteronol is maintained therein in stable form.

The procedures described in Example I are followed to prepare a syrup composition according to the formulations presented in the following examples.

Example 11 Percent Ingredient Amount 0.12 Isoproteronol sulfate ....gms 1.2000 48.5 Sucrose ..gms.. 485.3250 31.2 Glucose ..gms 311.5500 0.1 Ascorbic acid gm 1.0000 Deionized water, q.s ml 1000 Example III Percent Ingredient Amount 0.1 Isoproteronol sulfate gm 1.000 48.5 Sucrose gms 485.3250 31.2 Glucose gms 311.5500 0.05 Ascorbic acid gm 0.5000 Deionized water, q.s ml 1000 Example IV Percent Ingredient Amount 0.12 Isoproteronol sulfate gms 1.2000 48.5 Sucrose gms 485.3250 31.2 Glucose ..gms 311.5500 0.2 Ascorbic acid gms 2.000 Deionized water, q.s ml 1000 Example V Percent Ingredient Amount 0.015 Isoproteronol sulfate gm 0.1500 48.5 Sucrose gms 485.3250 31.2 Glucose gms 311.5500 0.1 Ascorbic acid gm 1.0000 'Deionized water, q.s ml 1000 4 Example VI Percent Ingredient Amount 0.06 Isoproteronol sulfate gm 0.6000 0.10 Ascorbic acid -gm 1.000 Deionized water, q.s ml 1000 Example VII Percent Ingredient Amount 0.06 Isoproteronol sulfate ..gm 0.6000 3.69 Calcium iodide gms 36.9306

(as C3126H20) 6.32 Ethanol (190 proof USP) gms 63.1578 0.1 Ascorbic acid gm 1.0000 5.4 Glycerin gms 53.9000 48.5 Sucrose gms 485.3250 31.2 Glucose gms 311.5500 0.8 Sodium cyclamate gms 8.0000 0.08 Sodium saccharin 0.8000 0.15 Honey imitation (Dodge & Olcot't Co.)

(Av-73) ml 1.5000 0.04 Floral mint (Alva Co. #3236) ml 0.3500 0.005 Yellow F.D.C. #5 g-m 0.0500 0.025 Caramel, acid proof NF ..gm.. 0.2500 Deionized water, q.s ml 1000 The calcium iodide is dissolved in 185 ml. of deionized water, and the solution is filtered through a kieselguhr bed (a bed of infusorial or diatomaceous earth). The sodium saccharin, sodium cyclamate, glycerin, glucose, sucrose and ascorbic acid are added and dissolved. The

honey and mint flavors are dissolved in the alcohol and the resulting solution is added to the syrup solution. The isoproteronol is dissolved in ml. of deionized water, and the resulting solution is added to the syrup solution; thereafter, the caramel and yellow F.D.C. colors are dis solved in 90 ml. of deionized water, and the resulting solution is added to the syrup solution. Deionized water is then added to the syrup solution to bring the volume up to 1000 ml., and the completed preparation is then filtered through a kieselguhr bed.

The sample of the prepared solution is assayed for isoproteronol content according to the method of photofiuorescenoe as determined with the aid of an Amico- Bowman Spectrophotofluorimeter. The apparatus fluoresces the active material at a particular wavelength of ultra-violet light. Only the undegraded isoproternol fluoresces at that particular ultra-violet wavelength. The isoproteronol content of the fresh syrup is 105.0% or 5% more than was calculated from the weighed amount. A sample kept at room temperature, after three months, shows an assay of 101.3% isoproteronol. After six months at room temperature a sample assays at 104.7% isoproteronol. six-month assay determination establishes that essentially no deterioration of isoproteronol has occurred.

Example VIII A formulation similar to the one described in Example V was prepared with the exception that isoproteronol sulfate was present in an amount of 0.08% or an absolute amount of 0.8000 gm./1000 ml. of final solution. Samples of the resulting syrup solution were held for observation and periodically assayed to determine the activity of isoproteronol present therein. The method of assay was the same as described in Example V. The initial isoproteronol content was 106%, and the content after six months at room temperature was 110% after one year at room temperature the content was determined as 114%. The variation in content was well within the errors of the method and does not affect the verified conclusion that stability of isoproteronol is unaffected after one year at room temperature. 7

The foregoing examples have illustrated the invention in various embodiments. The isoproteronol medicament employed in said examples has been described in the sulfate salt form. Other acid addition salts of the isopro teronol base may, of course, be employed in pharmaceutical formulations similar to those described herein. The practitioner may select an acid addition salt of isoproteronol so long as it is non-toxic and is inert to the other ingredients present in the compositions. Without intending to imply a limitation, the following salt forms may be used: the phosphate, the hydrochloride, the hydrobromide, the succinate, the cyclamate, the acetate and the like.

Others may practice the invention in any of the numerous ways which will be suggested by this disclosure to one skilled in the art. All such practice of the invention is considered to be a part hereof provided it falls within the scope of the appended claims.

I claim:

1. A stable, essentially aqueous, isoproteronol composition containing therein from about 0.02% to about 0.25% of a non-toxic acid addition salt of isoproteronol and at least about 0.05 ascorbic acid.

2. A stable, essentially aqueous, isoproteronol composition containing therein from about 0.02% to about 0.25 of a non-toxic acid addition salt of isoproteronol, at least about 0.05% ascorbic acid and sugar.

3. A stable, essentially aqueous, isoproteronol composition comprising sucrose, from about 0.02% to about 0.25% of isoproteronol sulfate and at least about 0.05% ascorbic acid.

4. A stable, essentially aqueous, isoproteronol composition comprising sucrose, glucose, from about 0.02% to about 0.25% of isoproteronol sulfate and at least about 0.05% ascorbic acid.

5. A stable, essentially aqueous, isoproteronol composition comprising about 50% sucrose, about 30% glucose, about 0.06% isoproteronol sulfate and about 0.1% ascorbic acid.

6. A method of stabilizing essentially aqueous compositions of isoproteronol which comprises adding from about 0.05% to about 0.25% of ascorbic acid to an aqueous solution containing from about 0.02% to about 0.25 of a non-toxic acid addition salt of isoproteronol.

References Cited in the file of this patent UNITED STATES PATENTS 2,212,831 Hoffman et a1. Aug. 27, 1940 2,623,002 Fricke Dec. 23, 1952 2,868,691 Porush et a1 Jan. 13, 1959 OTHER REFERENCES 

1. A STABLE, ESSENTIALLY AQUEOUS, ISOPROTERONOL COMPOSITION CONTAINING THEREIN FROM ABOUT 0.02% TO ABOUT 0.25% OF A NON-TOXIC ACID ADDITION SALT OF ISOPROTERONOL AND AT LEAST ABOUT 0.05% ASCORBIC ACID. 